(Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles

ABSTRACT

This invention relates to novel (Cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles and their use as CB2 cannabinoid receptor agonists, pharmaceutical compositions containing the same, and their use for the treatment of CB2 receptor mediated disorders or conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/143,523, filed Sep. 27, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/491,035, filed Apr. 19, 2017, now U.S. Pat. No.10,112,934, which is a continuation of U.S. patent application Ser. No.14/891,051, filed on Nov. 13, 2015, now U.S. Pat. No. 9,650,370, whichis a national stage application of International (PCT) PatentApplication Serial No. PCT/EP2014/060033, filed May 16, 2014, whichclaims the benefit of and priority to European Patent Application No.13168165.2, filed on May 17, 2013; the entire contents of theseapplications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to novel (Cyano-dimethyl-methyl)-isoxazoles- and-[1,3,4]thiadiazoles and their use as cannabinoid receptor 2 agonists(CB2 receptor agonists), pharmaceutical compositions containing thesame, and methods of using the same as agents for the treatment of CB2receptor mediated disorders or conditions.

BACKGROUND OF THE INVENTION

WO2008014199 and WO2008039645 discuss the CB2 receptor, and thetherapeutic uses of the CB2 receptor agonist compounds disclosedtherein. Further supporting evidence has more recently emerged in whichthe expression of CB2 in dorsal root ganglion neurons has beendemonstrated in multiple species (Anand et al., 2008 Pain 138: 667-680).Neuronal expression of CB2 has been shown to be altered underpathological pain conditions suggesting a key role for CB2 neuronalsignalling. A role for centrally located CB2 has been suggested byrecent reports of an effect of CB2 on addictive behaviour (Xi et al.,Nat. Neuroscience 2012, 14, 1160-1166; Morales & Bonci et al., NatureMed. 2012, 18, 504-505; Aracil-Fernandez et al., Neuropsychopharmacology2012, 37, 1749-1763) and other conditions in which maladaptiveimpulsivity plays a role (Navarrete et al., Br. J. Pharmacol. 2012, 165,260-273). A role of the hepatic CB2 in the pathogenesis ofsteatohepatitis and fibrotic liver diseases has also been suggested byseveral preclinical studies (Munoz-Luque et al., JPET 2008, 324,475-483; Reichenbach et al., JPET 2012, 340, 629-637, WO2011009883). Itis believed that the highly selective activation of the CB2 receptorwith an agonist may offer avenues of harnessing the beneficial effectswhile avoiding the adverse effects seen with dual CB1/CB2 cannabinoidreceptor agonists (see e.g. Expert Opinion on Investigational Drugs2005, 14, 695-703). It is desirable therefore to provide agonists of CB2with minimized CB1 activity.

WO2010036630, WO2010147792 and WO2010077836 disclose CB2 receptoragonists that are structurally closest to the compounds of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel (Cyano-dimethyl-methyl)-isoxazolesand -[1,3,4]thiadiazoles, namely

or a pharmaceutically acceptable salt thereof.

Compounds of the present invention are CB2 receptor agonists. Thedisclosed compounds are not only potent activators of the CB2 receptor(assay 1) but also show

-   -   1) no or low activation of the CB1 receptor (assay 2), and    -   2) no or low MDCK efflux (assay 3).

Thus, the present invention provides compounds which show a combinationof potency as CB2 receptor agonists, high selectivity against the CB1receptor, and low MDCK efflux.

It is demonstrated that the structurally closest compounds exemplifiedin WO2010036630, WO2010147792 and WO2010077836 do not have this balancedprofile of desirable properties. The compounds of the present inventionare therefore less likely to cause CB1 mediated side effects in vivo andto demonstrate in vivo efflux as compared to the closest prior artcompounds, while they are expected to be efficacious in various in vivomodels. Thus, they are expected to have a higher tolerability and aretherefore potentially more viable for human use.

GENERAL DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one skilled in the art in light of thedisclosure and the context.

Stereochemistry/Solvates/Hydrates

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc.) and racemates thereof aswell as mixtures in different proportions of the separate enantiomers,mixtures of diastereomers, or mixtures of any of the foregoing formswhere such isomers and enantiomers exist, as well as salts, includingpharmaceutically acceptable salts thereof and solvates thereof such asfor instance hydrates including solvates of the free compounds orsolvates of a salt of the compound.

Salts

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include salts from ammonia, L-arginine, betaine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine(2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol,2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine,1H-imidazole, lysine, magnesium hydroxide,4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine(2,2′,2″-nitrilotris(ethanol)), tromethamine, zinc hydroxide, aceticacid, 2.2-di-chloro-acetic acid, adipic acid, alginic acid, ascorbicacid, L-aspartic acid, benzenesulfonic acid, benzoic acid,2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclamic acid, decanoic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethane-sulfonic acid, ethylenediaminetetraacetic acid, formicacid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonicacid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid,hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid,isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine,maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid,methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionicacid, (−)-L-pyroglutamic acid, Salicylic acid, 4-amino-salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid. Further pharmaceutically acceptable salts can beformed with cations from metals like aluminium, calcium, lithium,magnesium, potassium, sodium, zinc and the like. (also seePharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., 1977, 66,1-19).

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts,) also comprise a part of the invention.

BIOLOGICAL ASSAYS

The biological activity of compounds was determined by the followingmethods.

A. In Vitro Testing of CB2 Potency: CB2 cAMP (Assay 1)

CHO cells expressing human CB2R (Euroscreen) were plated at a density of10,000 cells per well in 384 well plates and incubated overnight at 37°C. After removing the media, the cells were treated with test compoundsdiluted in stimulation buffer containing 1 mM IBMX, 0.25% BSA and 10 uMForskolin. The assay was incubated for 30 minutes at 37° C. Cells werelysed and the cAMP concentration was measured using DiscoverX-XS cAMPkit, following the manufacturer's protocol. In this setting, agonistswill decrease forskolin induced production of cAMP while inverseagonists will further increase forskolin induced production of cAMP.EC50 of agonists were calculated as follows. The maximal amount of cAMPproduced by forskolin compared to the level of cAMP inhibited by 1 uMCP55940 is defined as 100%. The EC50 value of each test compound wasdetermined as the concentration at which 50% of the forskolin-stimulatedcAMP synthesis was inhibited. Data was analyzed using a four-parameterlogistic model. (Model 205 of XLfit 4.0).

B. In Vitro Testing of CB1 Potency: CB1 cAMP (Assay 2)

CHO cells expressing human CB1 R (Euroscreen) were plated at a densityof 10,000 cells per well in 384 well plates and incubated overnight at37° C. After removing the media, the cells were treated with testcompounds diluted in stimulation buffer containing 1 mM IBMX, 0.25% BSAand 10 uM Forskolin. The assay was incubated for 30 minutes at 37° C.Cells were lysed and the cAMP concentration was measured usingDiscoverX-XS cAMP kit, following the manufacturer's protocol. In thissetting, agonists will decrease forskolin induced production of cAMPwhile inverse agonists will further increase forskolin inducedproduction of cAMP. EC50 of agonists were calculated as follows. Themaximal amount of cAMP produced by forskolin compared to the level ofcAMP inhibited by 1 uM CP55940 is defined as 100%. The EC50 value ofeach test compound was determined as the concentration at which 50% ofthe forskolin-stimulated cAMP synthesis was inhibited. Data was analyzedusing a four-parameter logistic model. (Model 205 of XLfit 4.0).

C. Assessment of Efflux in Madin-Darby Canine Kidney Cells Transfectedwith the Human MDR1 Gene (MDCK Assay) (Assay 3)

Apparent permeability coefficients (PE) of the compounds across theMDCK-MDR1 cell monolayers are measured (pH 7.4, 37° C.) inapical-to-basal (AB) and basal-to-apical (BA) transport direction. ABpermeability (PEAB) represents drug absorption from the blood into thebrain and BA permeability (PEBA) drug efflux from the brain back intothe blood via both passive permeability as well as active transportmechanisms mediated by efflux and uptake transporters that are expressedon the MDCK-MDR1 cells, predominantly by the overexpressed human MDR1P-gp. The compounds are assigned to permeability/absorption classes bycomparison of the AB permeabilities with the AB permeabilities ofreference compounds with known in vitro permeability and oral absorptionin the human. Identical or similar permeabilities in both transportdirections indicate passive permeation, vectorial permeability points toadditional active transport mechanisms. Higher PEBA than PEAB indicatesthe involvement of active efflux mediated by MDR1 P-gp. Active transportis concentration-dependently saturable.

MDCK-MDR1 cells (1-2×10e5 cells/1 cm2 area) are seeded on filter inserts(Costar transwell polycarbonate or PET filters, 0.4 μm pore size) andcultured (DMEM) for 7 days. Subsequently, the MDR1 expression is boostedby culturing the cells with 5 mM sodium butyrate in full medium for 2days. Compounds are dissolved in appropriate solvent (like DMSO, 1-20 mMstock solutions). Stock solutions are diluted with HTP-4 buffer (128.13mM NaCl, 5.36 mM KCl, 1 mM MgSO₄, 1.8 mM CaCl₂, 4.17 mM NaHCO₃, 1.19 mMNa₂HPO₄×7H₂O, 0.41 mM NaH₂PO₄×H₂O, 15 mM HEPES, 20 mM glucose, 0.25%BSA, pH 7.4) to prepare the transport solutions (0.1-300 μM compound,final DMSO<=0.5%). The transport solution (TL) is applied to the apicalor basolateral donor side for measuring A-B or B-A permeability (3filter replicates), respectively.

The receiver side contains the same buffer as the donor side. Samplesare collected at the start and end of experiment from the donor and atvarious time intervals for up to 2 hours also from the receiver side forconcentration measurement by HPLC-MS/MS or scintillation counting.Sampled receiver volumes are replaced with fresh receiver solution.

Biological Data

TABLE 1 Biological data of the compounds of the present invention inrelation to the structurally closest prior art compounds as obtained inassays 1, 2 and 3. MDCK efflux CB2 EC₅₀ CB1 EC₅₀ ratio Example Structure[nM] [nM] (BA/AB) Example 1

18     104,000 2.2 Example 7 in WO2010036630

15      28,000 6.9 Example 134 in WO2010036630

49      26,000 3.2 Example 2

104   >200,000 6.5 Example 1 in WO2010036630

88    >50,000 16   Example 17 in WO2010036630

30      8,600 4.8 Example 3

8  >200,000 2.5 Example 2 in WO2010036630

11     150,000 7.4 Example 38 in WO2010036630

 3.1    50,000 2.3 Example 133 WO2010036630

140   >200,000 4.7 Example 4

 0.36    39,400  0.75 Example 46 in WO2010147792

 0.27      923  0.63 Example 7 in WO2010147792

 0.68    8,082 1.2 Example 5

 0.23    2,500 5.1 Example 47 in WO2010147792

 0.85    3,100 14   Example 6

11      87,000 1.0 Example 190 in WO2010077836

 2.8    7,870 No data Example 7

25   >200,000 2.1 Example 30 in WO2010147792

 5.4   120,000 5.2 Example 8

 4.3    69,000 16  

Table 1 shows a direct comparison of the relevant biological propertiesof compounds of the present invention with those of the closest priorart disclosed in WO 2010036630, WO 2010147792 and WO 2010077836 whenassessed in assays 1, 2 and 3. Data demonstrate that compounds of thepresent invention have a more balanced profile in terms of CB2 potency,CB1 activity and MDCK efflux.

METHOD OF TREATMENT

The present invention is directed to compounds which are useful in thetreatment and/or prevention of a disease, disorder and/or conditionwherein the activation of cannabinoid receptor 2 is of therapeuticbenefit, including but not limited to the treatment and/or prevention ofpain; inflammatory diseases and/or associated conditions; andpsychiatric disorders and/or associated conditions.

In view of their pharmacological effect, the substances are suitable forthe treatment of a disease or condition selected from the listconsisting of

(1) acute pain such as for example toothache, perk and post-operativepain, traumatic pain, muscle pain, the pain caused by burns, sunburn,trigeminal neuralgia, pain caused by colic, as well as spasms of thegastro-intestinal tract or uterus; sprains;

(2) visceral pain such as for example chronic pelvic pain,gynaecological pain, pain before and during menstruation, pain caused bypancreatitis, peptic ulcers, interstitial cystitis, renal colic,cholecystitis, prostatitis, angina pectoris, pain caused by irritablebowel, non-ulcerative dyspepsia and gastritis, prostatitis, non-cardiacthoracic pain and pain caused by myocardial ischaemia and cardiacinfarct;

(3) neuropathic pain such as low back pain, hip pain, leg pain,non-herpetic neuralgia, post herpetic neuralgia, diabetic neuropathy,lumbosacral radiculopathy, nerve injury-induced pain, acquired immunedeficiency syndrome (AIDS) related neuropathic pain, head trauma, toxinand chemotherapy caused nerve injuries, phantom limb pain, multiplesclerosis, root avulsions, painful traumatic mononeuropathy, painfulpolyneuropathy, thalamic pain syndrome, post-stroke pain, centralnervous system injury, post surgical pain, carpal tunnel syndrome,trigeminal neuralgia, post mastectomy syndrome, postthoracotomysyndrome, stump pain, repetitive motion pain, neuropathic painassociated hyperalgesia and allodynia, alcoholism and other drug-inducedpain;

(4) inflammatory/pain receptor-mediated pain in connection with diseasessuch as for example osteoarthritis, rheumatoid arthritis, inflammatoryarthropathy, rheumatic fever, tendo-synovitis, bursitis, tendonitis,gout and gout-arthritis, traumatic arthritis, vulvodynia, damage to anddiseases of the muscles and fascia, juvenile arthritis, spondylitis,psoriasis-arthritis, myositides, dental disease, influenza and otherviral infections such as colds, systemic lupus erythematodes or paincaused by burns;

(5) tumour pain associated with cancers such as for example lymphatic ormyeloid leukaemia, Hodgkin's disease, non-Hodgkin's lymphomas,lymphogranulomatosis, lymphosarcomas, solid malignant tumours andextensive metastases;

(6) headache diseases of various origins, such as for example clusterheadaches, migraine (with or without aura) and tension headaches;

(7) sympathetically maintained pain like complex regional pain syndromeType I and II;

(8) painful conditions of mixed origin, such as for example chronic backpain including lumbago, or fibromyalgia, sciatica, endometriosis, kidneystones;

(9) inflammatory and/or oedematous diseases of the skin and mucousmembranes, such as for example allergic and non-allergic dermatitis,atopic dermatitis, psoriasis, burns, sunburn, bacterial inflammations,irritations and inflammations triggered by chemical or naturalsubstances (plants, insects, insect bites), itching; inflammation of thegums, oedema following trauma caused by burns, angiooedema or uveitis;

(10) Vascular and heart diseases which are inflammation-related likeartheriosclerosis including cardiac transplant atherosclerosis,panarteritis nodosa, periarteritis nodosa, arteritis temporalis, Wegnergranulomatosis, giant cell arthritis, reperfusion injury and erythemanodosum, thrombosis (e.g. deep vein thrombosis, renal, hepathic, portalvein thrombosis); coronary artery disease, aneurysm, vascular rejection,myocardial infarction, embolism, stroke, thrombosis including venousthrombosis, angina including unstable angina, coronary plaqueinflammation, bacterial-induced inflammation including Chlamydia-inducedinflammation, viral induced inflammation, and inflammation associatedwith surgical procedures such as vascular grafting including coronaryartery bypass surgery, revascularization procedures includingangioplasty, stent placement, endarterectomy, or other invasiveprocedures involving arteries, veins and capillaries, artery restenosis;

(11) inflammatory changes connected with diseases of the airways andlungs such as bronchial asthma, including allergic asthma (atopic andnon-atopic) as well as bronchospasm on exertion, occupationally inducedasthma, viral or bacterial exacerbation of an existing asthma and othernon-allergically induced asthmatic diseases; chronic bronchitis andchronic obstructive pulmonary disease (COPD) including pulmonaryemphysema, viral or bacterial exacerbation of chronic bronchitis orchronic obstructive bronchitis, acute adult respiratory distresssyndrome (ARDS), bronchitis, lung inflammation, allergic rhinitis(seasonal and all year round) vasomotor rhinitis and diseases caused bydust in the lungs such as aluminosis, anthracosis, asbestosis,chalicosis, siderosis, silicosis, tabacosis and byssinosis, exogenousallergic alveolitis, pulmonary fibrosis, bronchiectasis, pulmonarydiseases in alpha1-antitrypsin deficiency and cough;

(12) inflammatory diseases of the gastrointestinal tract includingCrohn's disease and ulcerative colitis, irritable bowel syndrome,pancreatitis;

(13) inflammation associated diseases of ear, nose, mouth and throatlike influenza and viral/bacterial infections such as the common cold,allergic rhinitis (seasonal and perennial), pharyngitis, tonsillitis,gingivitis, larhyngitis, sinusitis, and vasomotor rhinitis, fever, hayfever, thyroiditis, otitis, dental conditions like toothache,perioperative and post-operative conditions, trigeminal neuralgia,uveitis; iritis, allergic keratitis, conjunctivitis, blepharitis,neuritis nervi optici, choroiditis, glaucoma and sympathetic opthalmia,as well as pain thereof;

(14) diabetes mellitus and its comorbidities/effects/complications (suchas diabetic vasculopathy, hypertension, dyslipidemia, diabeticneuropathy, cardiomyopathy, diabetic retinopathy, eye disease, diabeticnephropathy, liver disease) and diabetic symptoms of insulitis (forexample hyperglycaemia, diuresis, proteinuria and increased renalexcretion of nitrite and kallikrein); and orthostatic hypotension;

(15) sepsis and septic shock after bacterial infections or after trauma;

(16) inflammatory diseases of the joints and connective tissue such asvascular diseases of the connective tissue, sprains and fractures, andmusculoskeletal diseases with inflammatory symptoms such as acuterheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatoidarthritis, spondylarthritis, and also osteoarthritis, and inflammationof the connective tissue of other origins, and collagenoses of allorigins such as systemic lupus erythematodes, scleroderma, polymyositis,dermatomyositis, Sjögren syndrome, Still's disease or Felty syndrome; aswell as vascular diseases such as panarteriitis nodosa, polyarthritisnodosa, periarteriitis nodosa, arteriitis temporalis, Wegner'sgranulomatosis, giant cell arteriitis, arteriosclerosis and erythemanodosum;

(17) diseases of and damage to the central nervous system such as forexample cerebral oedema and the treatment and prevention of psychiatricdiseases such as depression, for example, and for the treatment andprevention of epilepsy;

(18) disorders of the motility or spasms of respiratory, genito-urinary,gastro-intestinal including biliary or vascular structures and organs;

(19) post-operative fever;

(20) arteriosclerosis and related complaints;

(21) diseases of the genito-urinary tract such as for example urinaryincontinence and related complaints, benign prostatic hyperplasia andhyperactive bladder, nephritis, cystitis (interstitial cystitis);

(22) morbid obesity and related complaints including sleep apnea, eatingdisorders and complications;

(23) neurological diseases such as cerebral oedema and angioedema,cerebral dementia like e.g. Parkinson's and Alzheimer's disease, seniledementia; multiple sclerosis, epilepsy, temporal lobe epilepsy, drugresistant epilepsy, stroke, myasthenia gravis, brain and meningealinfections like encephalomyelitis, meningitis, HIV as well asschizophrenia, delusional disorders, autism, affective disorders and ticdisorders, Huntington's disease;

(24) cognitive impairments associated with schizophrenia, Alzheimer'sDisease and other neurological and psychiatric disorders. With respectto Alzheimer's disease, the compounds of general formula (I) may also beuseful as disease modifying agent;

(25) work-related diseases like pneumoconiosis, including aluminosis,anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis,tabacosis and byssinosis;

(26) various other disease states and conditions like epilepsy, septicshock e.g. as antihypovolemic and/or antihypotensive agents, sepsis,osteoporosis, benign prostatic hyperplasia and hyperactive bladder,nephritis, pruritis, vitiligo, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, allergic skin reactions, mixed-vascular and non-vascularsyndromes, septic shock associated with bacterial infections or withtrauma, central nervous system injury, tissue damage and postoperativefever, syndromes associated with itching;

(27) anxiety, depression, epilepsy, impulsivity, conditions in whichmaladaptive impulsivity plays a role, anorexia nervosa, binge eating,drug abuse (e.g. cocaine), alcohol abuse, nicotine abuse, borderlinepersonality disorders, attention deficit and hyperactive disorders andneurodegenerative diseases such as dementia, Alzheimer's disease andParkinson's disease. The treatment of affective disorders includesbipolar disorders, e.g. manic-depressive psychoses, extreme psychoticstates, e.g. mania and excessive mood swings for which a behaviouralstabilization is being sought. The treatment of anxiety states includesgeneralized anxiety as well as social anxiety, agoraphobia and thosebehavioural states characterized by social withdrawal, e.g. negativesymptoms;

(28) diseases involving pathological vascular proliferation, e.g.angiogenesis, restenosis, smooth muscle proliferation, endothelial cellproliferation and new blood vessel sprouting or conditions requiring theactivation of neovascularization. The angiogenic disease may for examplebe age-related macular degeneration or vascular proliferation associatedwith surgical procedures, e.g. angioplasty and AV shunts. Other possibleuses are the treatments of arteriosclerosis, plaque neovascularization,hypertrophic cardiomyopathy, myocardial angiogenesis, valvular disease,myocardiac infarction, coronary collaterals, cerebral collaterals andischemic limb angiogenesis;

(29) inflammatory and fibrotic liver diseases including insulinresistance, non-alcoholic steatohepatitis, liver cirrhosis,hepatocellular carcinoma, primary biliary cirrhosis, primary sclerosingcholangitis, alcoholic liver disease, drug-induced liver injury, viralhepatitis.

According to another embodiment, the compounds of the present inventionare useful for the treatment and/or prevention of neuropathic pain.

Another aspect is the use of a compound of the present invention for thetreatment and/or prevention of pain.

The present invention also relates to the use of the compounds for thetreatment of neuropathic pain associated with a disease or conditionselected from the list consisting of diabetic peripheral neuropathy,lumbosacral radiculopathy and post herpetic neuralgia.

A further aspect of the present invention is a method for the treatmentand/or prevention of a disease or condition as mentioned above, whichmethod comprises the administration of an effective amount of a compoundof the present invention to a human being.

The present invention also relates to a compound of the invention as amedicament.

Furthermore, the present invention relates to the use of the compoundsfor the treatment and/or prevention of a disease, disorder or conditionwherein the activation of the cannabinoid receptor 2 is of therapeuticbenefit.

The dose range of the compounds of the invention applicable per day isusually from 1 to 1000 mg, preferably from 5 to 800 mg, more preferablyfrom 25 to 500 mg. Each dosage unit may conveniently contain from 1 to1000 mg, preferably 25 to 500 mg.

The actual pharmaceutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the combination will be administered at dosages andin a manner which allows a pharmaceutically effective amount to bedelivered based upon patient's unique condition.

PHARMACEUTICAL COMPOSITIONS

Suitable preparations for administering the compounds of the presentinvention will be apparent to those with ordinary skill in the art andinclude for example tablets, pills, capsules, suppositories, lozenges,troches, solutions, syrups, elixirs, sachets, injectables, inhalatives,powders, etc. The content of the pharmaceutically active compound(s)should be in the range from 0.1 to 95 wt.-%, preferably 5.0 to 90 wt.-%of the composition as a whole. Suitable tablets may be obtained, forexample, by mixing one or more compounds of the present invention withknown excipients, for example inert diluents, carriers, disintegrants,adjuvants, surfactants, binders and/or lubricants. The tablets may alsoconsist of several layers.

COMBINATION THERAPY

Compounds according to the present invention can be combined with othertreatment options known to be used in the art in connection with atreatment of any of the indications the treatment of which is in thefocus of the present invention.

Among such treatment options that are considered suitable forcombination with the treatment according to the present inventions are:

-   -   non-steroidal antiinflammatory drugs (NSAIDs) including COX-2        inhibitors;    -   opiate receptor agonists;    -   Cannabionoid agonists or inhibitors of the endocannabinoid        pathway    -   Somatostatin receptor agonists    -   Sodium channel blockers;    -   N-type calcium channel blockers;    -   serotonergic and noradrenergic modulators;    -   corticosteroids;    -   histamine H1, H2, H3 and H4 receptor antagonists;    -   proton pump inhibitors;    -   leukotriene antagonists and 5-lipoxygenase inhibitors;    -   local anesthetics;    -   VR1 agonists and antagonists;    -   Nicotinic acetylcholine receptor agonists;    -   P2X3 receptor antagonists;    -   NGF agonists and antagonists or anti-NGF antibodies;    -   NK1 and NK2 antagonists;    -   Bradykinin B1 antagonists    -   CCR2 antagonists    -   iNOS or nNOS or eNOS inhibitors    -   NMDA antagonist;    -   potassium channel modulators;    -   GABA modulators;    -   mGluR antagonists and modulators;    -   serotonergic and noradrenergic modulators;    -   anti-migraine drugs;    -   neuropathic pain drugs such as pregabaline or duloxetine;    -   antidiabetic drugs and insulin.

In the following representative examples of such treatment options shallbe given:

-   -   Non-steroidal antiinflammatory drugs (NSAIDs) including COX-2        inhibitors: propionic acid derivatives (alminoprofen,        benoxaprofen, bucloxic acid, carprofen, fenhufen, fenoprofen,        flubiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen,        naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,        tiaprofenic acid, and tioxaprofen), acetic acid derivatives        (indomethacin, acemetacin, alclofenac, clidanac, diclofenac,        fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,        isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin,        and zomepirac), fenamic acid derivatives (meclofenamic acid,        mefenamic acid, and tolfenamic acid), biphenyl-carboxylic acid        derivatives, oxicams (isoxicam, meloxicam, piroxicam, sudoxicam        and tenoxican), salicylates (acetyl salicylic acid,        sulfasalazine) and the pyrazolones (apazone, bezpiperylon,        feprazone, mofebutazone, oxyphenbutazone, phenylbutazone), and        the coxibs (celecoxib, valecoxib, rofecoxib and etoricoxib) and        the like;    -   Antiviral drugs like acyclovir, tenovir, pleconaril, peramivir,        pocosanol and the like.    -   Antibiotic drugs like gentamicin, streptomycin, geldanamycin,        doripenem, cephalexin, cefaclor, ceftazichine, cefepime,        erythromycin, vancomycin, aztreonam, amoxicillin, bacitracin,        enoxacin, mafenide, doxycycline, chloramphenicol and the like;    -   Opiate receptor agonists: morphine, propoxyphene (Darvon),        tramadol, buprenorphin and the like;    -   Glucocorticosteroids such as bethamethasone, budesonide,        dexamethasone, hydrocortisone, methylprednisolone, prednisolone,        prednisone, triamcinolone and deflazacort; immunosuppressive,        immunomodulatory, or cytsostatic drugs including but not limited        to hydroxychlorquine, D-penicillamine, sulfasalizine, auranofin,        gold mercaptopurine, tacrolimus, sirolimus, mycophenolate        mofetil, cyclosporine, leflunomide, methotrexate, azathioprine,        cyclophosphamide and glatiramer acetate and novantrone,        fingolimod (FTY720), minocycline and thalidomide and the like;    -   anti-TNF antibodies or TNF-receptor antagonists such as but not        limited to Etanercept, Infliximab, Adalimumab (D2E7), CDP 571,        and Ro 45-2081 (Lenercept), or biologic agents directed against        targets such as but not limited to CD-4, CTLA-4, LFA-1, IL-6,        ICAM-1, C5 and Natalizumab and the like;    -   IL-1 receptor antagonists such as but not limited to Kineret;    -   Sodium channel blockers: carbamazepine, mexiletine, lamotrigine,        tectin, lacosamide and the like.    -   N-type calcium channel blockers: Ziconotide and the like;    -   Serotonergic and noradrenergic modulators: paroxetine,        duloxetine, clonidine, amitriptyline, citalopram;    -   Histamine H1 receptor antagonists: bromophtniramint,        chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,        diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,        methdiJazine, promethazine, trimeprazine, azatadine,        cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,        terfenadine, loratadine, cetirizine, deslo-ratadine,        fexofenadine and levocetirizine and the like;    -   Histamine H2 receptor antagonists: cimetidine, famotidine and        ranitidine and the like;    -   Histamine H3 receptor antagonists: ciproxifan and the like    -   Histamine H4 receptor antagonists: thioperamide and the like    -   Proton pump inhibitors: omeprazole, pantoprazole and        esomeprazole and the like;    -   Leukotriene antagonists and 5-lipoxygenase inhibitors:        zafirlukast, mon-telukast, pranlukast and zileuton and the like;    -   Local anesthetics such as ambroxol, lidocaine and the like;    -   Potassium channel modulators, like retigabine;    -   GABA modulators: lacosamide, pregabalin, gabapentin and the        like;    -   Anti-migraine drugs: sumatriptan, zolmitriptan, naratriptan,        eletriptan, telcegepant and the like;    -   NGF antibodies such as RI-724 and the like;    -   Antidiabetic medication: Metformin, SUs, TZDs, GLP1 agonists,        DPP4 inhibitor, SGLT2 inhibitor, insulin.

Combination therapy is also possible with new principles for thetreatment of pain.

The combination of compounds is preferably a synergistic combination.Synergy, as described for example by Chou and Talalay, Adv. EnzymeRegul. 22:27-55 (1984), occurs when the effect of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at suboptimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased pharmacological effect, or some other beneficialeffect of the combination compared with the individual components.

EXPERIMENTAL SECTION List of Abbreviations

-   -   RT room temperature    -   BOC tert-butoxy-carbonyl-    -   EI-MS electron induced mass spectrometry    -   ESI-MS electrospray ionisation mass spectrometry    -   aq. aqueous    -   MS mass spectrum    -   MeOH methanol    -   EtOH ethanol    -   EE ethylacetate    -   DMF N,N-dimethylformamide    -   DCM dichloromethane    -   TBME tert-butylmethylether    -   THF tetrahydrofuran    -   Me-THF methyl-tetrahydrofuran    -   DIPEA N,N-diisopropyl ethylamine    -   HATU N,N,N′, N′-tetramethyl-o-(7-azabenzotriazol-1-yl)uronium        hexafluorophosphate    -   Rt retention time    -   d day(s)    -   sat. saturated    -   ACN acetonitrile    -   TFA trifluoroacetic acid

HPLC-Methods:

-   -   Method Name: A    -   Column: Xbridge C18, 4.6×30 mm, 3.5 μm    -   Column Supplier: Waters

Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% NH₃] [ACN][mL/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 560

-   -   Method Name: B    -   Column: Sunfire C18, 2.1×30 mm, 2.5 μm    -   Column Supplier: Waters

Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% TFA] [ACN][mL/min] [° C.] 0.0 99 1 1.5 60 0.02 99 1 1.5 60 1.00 0 100 1.5 60 1.100 100 1.5 60

-   -   Method Name: C    -   Column: XBridge C18, 4.6×30 mm, 3.5 μm    -   Column Supplier: Waters

Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% NH₃][Methanol] [mL/min] [° C.] 0.0 95 5 4 60 0.15 95 5 4 60 1.7 0 100 4 602.1 0 100 4 60

-   -   Method Name: D    -   Column: StableBond C18, 4.6×30 mm, 3.5 μm    -   Column Supplier: Agilent

Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% TFA][Methanol] [mL/min] [° C.] 0.0 95 5 4 60 0.15 95 5 4 60 1.7 0 100 4 602.1 0 100 4 60

-   -   Method Name: E    -   Column: XBridge C18, 4.6×30 mm, 3.5 μm    -   Column Supplier: Waters

Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% NH₃] [ACN][mL/min] [° C.] 0.0 95 5 4 60 0.15 95 5 4 60 1.7 0 100 4 60 2.25 0 100 460

-   -   Method Name: F    -   Column: Sunfire C18, 3×30 mm, 2.5 μm    -   Column Supplier: Waters

Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% TFA] [ACN][mL/min] [° C.] 0.0 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.250 100 3 60 1.40 0 100 3 60

-   -   Method Name: G    -   Column: Sunfire C18, 4.6×30 mm, 3.5 μm    -   Column Supplier: Waters    -   Device description: Agilent 1100 with DAD, Waters Autosampler        and MS-Detector

Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% TFA] [ACN][mL/min] [° C.] 0.0 98 2 2.5 60 1.5 0 100 2.5 60 1.8 0 100 2.5 60

-   -   Method Name: H    -   Column: XBridge C18, 3.0×30 mm, 2.5 μm    -   Column Supplier: Waters    -   Device description: Waters Acquity with DA- and MS-Detector and        CTC Autosampler

Gradient/Solvent % Sol % Sol Flow Temp Time [min] [H₂O, 0.1% NH₃] [ACN][mL/min] [° C.] 0.0 98 2 2.0 60 1.2 0 100 2.0 60 1.4 0 100 2.0 60

Preparation of Intermediates Intermediate 12-Methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid

For additional analytical data: see WO2010036630

Step 1: Tetrahydropyran-4-ol

To 75 g (0.75 mol) of tetrahydropyran-4-one in THF (150 mL) is added asuspension of 28.4 g (0.75 mol) LiAlH₄ in THF (600 mL) under nitrogenatmosphere maintaining the temperature below 30° C. with the aid of anice-bath. Then the reaction is allowed to warm to RT and stirred for 5h. The reaction is quenched by addition of sat. aq. NH₄Cl solution untileffervescence ceased. The resulting precipitate is removed by filtrationthrough Celite® and washed with THF (150 mL). The filtrate isconcentrated under reduced pressure to afford 71.1 g oftetrahydropyran-4-ol. Yield: 92%.

Step 2: Toluene-4-sulfonic acid tetrahydropyran-4-yl ester

To 133 g (1.31 mol) of tetrahydropyran-4-ol in pyridine (1.5 L) areadded 373 g (1.95 mol) of p-toluenesulfonylchloride portionwise at 10°C. After complete addition the reaction is allowed to warm to RT andstirred for 18 h. The reaction is poured onto a stirred mixture of aq.HCl/ice. The resulting precipitate is isolated by filtration anddissolved in DCM (1 L). The organic layer is washed with 1 M aq. HClsolution (1 L), followed by sat. aq. NaHCO₃ solution (1 L) and is thendried over Na₂SO₄. Filtration and concentration of the filtrate underreduced pressure gives 300 g of toluene-4-sulfonic acidtetrahydropyran-4-yl ester. Yield: 90%; ESI-MS: 257 [M+H]⁺

Step 3: Thioacetic acid S-(tetrahydro-pyran-4-yl) ester

To 300 g (1.175 mol) of toluene-4-sulfonic acid tetrahydropyran-4-ylester in DMF (3 L) are added 268 g (2.35 mol) potassium thioacetate,followed by a catalytic amount of NaI (0.12 g, 10 mol %) at RT. Aftercomplete addition, the reaction is heated to 50° C. for 20 h. Thereaction mixture is partitioned between TBME (3 L) and water (3 L), theaq. layer is extracted with TBME (2 L), then saturated with NaCl andextracted again with TBME (2×2 L). The combined organic extracts aredried over Na₂SO₄, filtered and the solvent is removed under reducedpressure to afford 153 g of thioacetic acid S-(tetrahydro-pyran-4-yl)ester. Yield: 81%; ESI-MS: 161 [M+H]⁺

Step 4: 2-Methyl-2-(tetrahydro-pyran-4-ylsulfanyl)-propionic acid ethylester

A solution of 153 g (0.96 mol) of thioacetic acidS-(tetrahydro-pyran-4-yl) ester in EtOH (3.5 L) is degassed withnitrogen over 0.5 h and 125 g (2.23 mol) of KOH are added. Then asolution of 250 mL (1.68 mol) of ethyl α-bromoisobutyrate in EtOH (1 L)are added over 0.5 h, during which the temperature increased to 40° C.The reaction is stirred for 18 h at RT under a nitrogen atmosphere. Thereaction mixture is filtered, the solid is washed with EtOH (0.5 L) andthe filtrate is concentrated under reduced pressure. The crude materialis dryloaded onto silica and purified by dry-flash column chromatography(silica, eluent: nheptanes, 2-10% EE) to afford 158 g of2-methyl-2-(tetrahydro-pyran-4-ylsulfanyl)-propionic acid ethyl ester.Yield: 71%; ESI-MS: 233 [M+H]⁺

Step 5: 2-Methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid ethylester

To 158 g (0.68 mol) of2-methyl-2-(tetrahydro-pyran-4-ylsulfanyl)-propionic acid ethyl ester indioxane/water (4/1, 1.6 L) are added 835 g (1.35 mol) of OXONE® inportions over 50 min. The reaction mixture is stirred at RT for 18 h.The solid is removed by filtration and washed with dioxane (1 L). Thecombined filtrates are concentrated under reduced pressure. The residueis dissolved in EE (1.5 L) and washed with water (1 L). The organiclayer is dried over Na₂SO₄, filtered and the solvent is removed underreduced pressure to afford 166 g of2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid ethyl ester.Yield: 92%; ESI-MS: 265 [M+H]⁺

Step 6: 2-Methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid

To 166 g (0.63 mol) of2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid ethyl ester inTHF/water (4/1, 1.66 L) are added 50.5 g (1.26 mol) of NaOH pellets inportions over 20 min. The reaction is stirred at RT for 2.5 d. Theorganic solvent is removed under reduced pressure and the aq. residue isdiluted with water (2 L) and washed with DCM (2 L). The aq. layer isacidified to pH 1-2 with concentrated HCl and then extracted with DCM(3×2 L). The acidic aqueous layer is further saturated with NaCl andextracted again with DCM (6×2 L). The combined organic extracts areconcentrated under reduced pressure to give 123 g of2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid. Yield: 83%;ESI-MS: 235 [M+H]⁻

Intermediate 22-Methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid

For additional analytical data: see WO2010036630

Step 1: (Tetrahydro-pyran-4-yl)-methanol

To 250 mL of LiAlH₄ (2.3 M solution in THF, 0.58 mol) in THF (200 mL) isadded dropwise a solution of 130 mL (0.974 mol) oftetrahydro-pyran-4-carboxylic acid methyl ester in THF (900 mL) undernitrogen atmosphere. The temperature is kept at 40-45° C. with anice-bath. Upon complete addition, the reaction is stirred at RT for 1.5h. The reaction is cooled in an ice-bath and quenched with addition ofwater (22 mL), 15% aq. NaOH solution (21 mL) and water (66 mL). Theresulting precipitate is removed by filtration through Celite® and isrinsed with THF (300 mL). The filtrate is concentrated under reducedpressure to afford 102.5 g of (tetrahydro-pyran-4-yl)-methanol. Yield:91%

Step 2: Synthesis of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethylester

Prepared as described by adaptation of the following literaturereference: Radziszewski, J. G. et al. J. Am. Chem. Soc. 1993, 115, 8401.

To 97 g (810 mmol) of (tetrahydro-pyran-4-yl)-methanol in2-methyltetrahydrofuran (190 mL) are added 165 mL of 50% aq. NaOHsolution. To this stirred suspension is added dropwise with cooling asolution of p-toluene-sulfonylchloride (283 g, 1.46 mol) in2-methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35° C.for 18h. The suspension is poured into a mixture of ice-water (280 mL)and aq. HCl solution (37%, 203 mL). After addition of methylcyclohexane(1.4 L) and further ice-water (0.2 L), the reaction mixture is stirredfor 2 h in an ice-bath. The resulting crystalline precipitate isisolated by filtration and washed with methylcyclohexane (0.5 L) andwater (0.5 L). Drying under reduced pressure at 40° C. gave 216 g oftoluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester. Yield: 99%;ESI-MS: 271 [M+H]⁺

Step 3: Thioacetic acid S-(tetrahydro-pyran-4-ylmethyl) ester

Prepared as described by adaptation of the following literaturereference: Watson, R. J. et al. Tetrahedron Lett. 2002, 43, 683-685.

To 224 g (0.83 mol) of toluene-4-sulfonic acidtetrahydro-pyran-4-ylmethyl ester in methyl isobutylketone (1.6 L) areadded 189 g (1.66 mol) of potassium thioacetate. The suspension isstirred at 70° C. for 4.5 h. The reaction mixture is cooled to RT andwater (1.8 L) is added. The organic layer is washed with 10% aq. K₂CO₃solution (1.8 L) and water (1 L). The organic layer is filtered throughCelite® (20 g), activated charcoal (20 g) and Na₂SO₄ (20 g) and thefiltrate is concentrated under reduced pressure. The residual oil isazeotroped with methylcyclohexane (200 mL) and n-heptanes (250 mL) toafford 138 g of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl) ester.Yield: 96%; ESI-MS: 175 [M+H]⁺

Step 4: 2-Methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acidethyl ester

A 90 g (516 mmol) of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl)ester in toluene (500 mL) under nitrogen atmosphere is cooled in anice-bath. A solution of sodium ethoxide in EtOH (21%, 231 mL) is addedand the reaction stirred for 50 min. Then 76 mL (516 mmol) of ethylα-bromoisobutyrate are added and the reaction stirred for 1 h. To thereaction mixture are added glacial acetic acid (8.9 mL) and water (500mL). The organic layer is separated and washed with water (500 mL). A3-neck round bottom flask is charged with water (500 mL), OOXONE® (477g, 775 mmol) and tetrabutylammonium-hydrogensulfate (5 g, 15 mmol) andthe organic layer is added. The reaction mixture is stirred for 2 d atRT. The solids are removed by filtration and the layers of the filtrateare separated. The organic layer is washed with water (2×500 mL). Thesolvent is removed under reduced pressure and further azeotroped withtoluene to give 125 g of2-methyl-2-(tetrahydropyran-4-ylmethanesulfonyl)-propionic acid ethylester. Yield: 87%; ES-MS: 279 [M+H]⁺

Step 5: 2-Methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid

To 123 g (0.44 mol) of2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid ethylester in THF (450 mL) are added 663 mL of 2M aq. NaOH solution (1.33mol). The reaction is stirred at RT for 1 h. To the reaction mixture isadded TBME (1.25 L) and the layers are separated. The aq. layer iscooled in an ice bath and then acidified with 37% aq. HCl solution (123mL). The resulting precipitate is isolated by filtration, washed withwater (200 mL) and dried under reduced pressure at 50° C. to afford 101g of 2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid.Yield: 91%; ESI-MS: 251 [M+H]⁺

Intermediate 3 Synthesis of2-Methyl-2-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid

For additional analytical data: see WO2010036630

Step 1: Tetrahydro-pyran-4-carbaldehyde

To 5.00 g (43.0 mmol) of (tetrahydro-pyran-yl)-methanol in DCM (50 mL)are added 67 mg of 2,2,6,6-tetramethyl-1-piperidinyloxy (0.43 mmol), asolution of 9.04 g (108 mmol) NaHCO₃ in water (70 mL) and 512 mg (4.30mmol) of potassium bromide at 20° C. The suspension is cooled in an icebath to 4° C. Then a solution of 23.5 mL sodium hypochlorite (10-15%free chlorine; 47.4 mmol) is added in 35 min. The suspension is stirredfor 30 min at 4-9° C. and further 45 min to reach 17° C. 4.80 mL sodiumhypochlorite (10-15% free chlorine) is added within 15 min. The reactionis stirred for 16 h at RT. The suspension is filtered and the layers areseparated. The aq. layer is washed with 50 mL DCM, the combined organiclayers are washed with 50 mL water. The solvent is removed under reducedpressure to afford 3.00 g of tetrahydro-pyran-4-carbaldehyde. Yield:61%; ESI-MS: 113 [M+H]⁻

Step 2: 2-Methyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid

To 0.90 g (8.76 mmol) of 2-amino-2-methyl-propionic in 10 mL MeOH isadded at RT 1.00 g (8.76 mmol) of tetrahydro-pyran-4-carbaldehyde. After25 min Pd(OH)₂ (310 mg, w=20%) is added. The reaction is stirred at 50°C. and 2757 kPa hydrogen pressure for 18 h. 10 mL of acetonitrile and 20mL of water are added, filtered through celite to remove the catalystand washed with water. The solvent is removed under reduced pressure togive 1.62 g of crude product, which is recrystallized from MeOH andwater to afford 1.24 g of2-methyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid. Yield:70%; ESI-MS: 202 [M+H]⁺

Step 3:2-Methyl-2-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid1.00 g (4.97 mmol) of2-methyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid issuspended in 20 mL of EtOH. 350 mg Pd(OH)₂ (0.50 mmol, w=20%) are added,followed by 0.74 mL of formaldehyde (9.88 mmol; 37% in water). Thesuspension is stirred for 24 h at 100° C. and 2916 kPa hydrogenpressure. The reaction mixture is filtered through celite and washedwith EtOH. The solvent is removed under reduced pressure to afford 0.90g of 2-methyl-2-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-propionicacid. Yield: 84%; ESI-MS: 216 [M+H]⁺

Intermediate 4 Synthesis of2-[(1-Methanesulfonyl-piperidin-4-yl)-methyl-amino]-2-methyl-propionicacid

Step 1: (1-Methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butylester

5.00 g (25.0 mmol) of BOC-4-aminopiperidine are dissolved in pyridine(19.8 mL) and cooled in an ice bath. 2.13 mL (27.5 mmol) ofmethanesulfonyl chloride are added slowly. The reaction is stirred at RTfor 16 h. After diluting with water, the reaction is extracted with DCM.Organic layers are washed with water, dried with MgSO₄ and filtered. Thesolvent is removed under reduced pressure to afford 6.30 g of(1-Methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester.Yield: 91%; ESI-MS: 279 [M+H]⁺

Step 2: 1-Methanesulfonyl-piperidin-4-ylamine

6.30 g (22.63 mmol) of (1-methanesulfonyl-piperidin-4-yl)-carbamic acidtert-butyl ester are dissolved in DCM (74 mL) and 17.4 mL (226 mmol) TFAare added. The reaction is stirred at RT for 16 h. The solvent isremoved under reduced pressure. The crude product is diluted withdiethylether at 40° C., the precipitate is filtered, washed with waterand dried. The product is dissolved in MeOH, polymer supportedhydrogencarbonate (PL-HCO₃ MP Resin, Agilent Technologies) is added andthe suspension is stirred for a few minutes. The resin is filtered andthe solvent is removed under reduced pressure to afford 4.00 g of1-methanesulfonyl-piperidin-4-ylamine. Yield: 99%; ESI-MS: 179 [M+H]⁺;HPLC (Rt): 0.26 min (method E)

Step 3: 2-(1-Methanesulfonyl-piperidin-4-ylamino)-2-methyl-propionicacid ethyl ester 2.40 g (13.5 mmol) of1-methanesulfonyl-piperidin-4-ylamine are dissolved in DMF (32.8 mL).5.58 g (40.4 mmol) of K₂CO₃, 3.06 mL (20.2 mmol)ethyl-2-bromoisobutyrate and 1.12 g (6.73 mmol) of KI are added at RT.The reaction is stirred 16 h. Additional ethyl-2-bromoisobutyrate (3.06mL) and KI (1.12 g) are added and the reaction mixture is stirred forfurther 16 h. Water and sat. aq. K₂CO₃ solution is added, the aqueouslayer extracted with EE. The combined organic layers are dried overMgSO₄ and filtered. The solvent is removed under reduced pressure toafford the crude product, which is purified by silica gel chromatography(eluent: EE/MeOH 95/5) to afford 0.56 g of2-(1-methanesulfonyl-piperidin-4-ylamino)-2-methyl-propionic acid ethylester. Yield: 14%; ESI-MS: 293 [M+H]⁺; HPLC (Rt): 0.97 min (method E)

Step 4:2-[(1-Methanesulfonyl-piperidin-4-yl)-methyl-amino]-2-methyl-propionicacid ethyl ester

0.71 g (2.43 mmol) of2-(1-methynesulfonyl-piperidin-4-ylamino)-2-methyl-propionic acid ethylester are dissolved in DMF (5.92 mL). 1.51 g (10.9 mmol) K₂CO₃ and 227μl (3.64 mmol) methyl iodide are added at RT. The reaction is stirredfor 2 d. Additional methyl iodide (227 μl) is added an stirring iscontinued for 5 h. The solvent is removed under reduced pressure. Theresidue is dissolved in EE and is washed with sat. aq. NaHCO₃ solutionand brine. Organic layers are separated, dried over MgSO₄, filtered andthe solvent is removed under reduced pressure to afford 0.76 g of crude2-[(1-methanesulfonyl-piperidin-4-yl)-methyl-amino]-2-methyl-propionicacid ethyl ester, which is used without further purification. ESI-MS:307[M+H]⁺; HPLC (Rt): 1.09 min (method E)

Step 5:2-[(1-Methanesulfonyl-piperidin-4-yl)-methyl-amino]-2-methyl-propionicacid

0.76 g (2.48 mmol) of2-[(1-methanesulfonyl-piperidin-4-yl)-methyl-amino]-2-methyl-propionicacid ethyl ester are dissolved in EtOH (14.3 mL) and 3.72 mL (14.9 mmol)4 N NaOH are added at RT. The reaction is refluxed for 16 h. The solventis removed under reduced pressure, the residue is diluted with water andneutralized to pH 7 and lyophilized. The product is dissolved in acetoneand filtered. The solvent is removed under reduced pressure to afford0.26 g of2-[(1-methanesulfonyl-piperidin-4-yl)-methyl-amino]-2-methyl-propionicacid. Yield: 37%; ESI-MS: 279 [M+H]⁺; HPLC (Rt): 0.23 min (method D)

Intermediate 5 2-Methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionicacid

For additional analytical data: see WO2010036630

Step 1: 2-Acetylsulfanyl-2-methyl-propionic acid ethyl ester

To a solution of ethyl α-bromoisobutyrate (62 g, 0.32 mol) in DMF (500mL) at room temperature is added potassium thioacetate (72 g, 0.63 mol).The reaction is stirred for 16 h and then concentrated under reducedpressure. The residue is diluted with a 2 M aq. HCl solution (500 mL)and extracted with EE (3×500 mL). The organic fractions are combined,washed with brine (300 mL), dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by chromatography on silica elutingwith heptanes/DCM provides 44 g of 2-acetylsulfanyl-2-methyl-propionicacid ethyl ester. Yield: 73%; ESI-MS: 191 [M+H]⁺

Step 2: 2-Methyl-2-(4,4,4-trifluoro-butylsulfanyl)-propionic acid ethylester

To a solution of 149 g (0.785 mol) of2-acetylsulfanyl-2-methyl-propionic acid ethyl ester in EtOH (1.2 L,degassed under nitrogen for 1 h) are added 169.7 g (0.105 mol) of sodiummethoxide, followed by a solution of 150 g (0.785 mol) of4-bromo-1,1,1-trifluoro-butane. The reaction is heated to 85° C. for 3d. The solvent is removed under reduced pressure. The residue isdissolved in DCM (1 L) and washed with saturated aq. NaHCO₃ solution(2×1 L). The organic layer is dried over Na₂SO₄, filtered and thefiltrate is concentrated under reduced pressure to afford 171 g of2-methyl-2-(4,4,4-trifluoro-butylsulfanyl)-propionic acid ethyl ester.Yield: 84%; ESI-MS: 259 [M+H]⁺

Step 3: 2-Methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionic acidethyl ester

To a solution of 220 g (0.852 mol) of2-methyl-2-(4,4,4-trifluoro-butylsulfanyl)-propionic acid ethyl ester indioxane/water (1/1, 4 L) are added 1047 g (1.703 mol) of OXONE® inportions over 0.5 h at RT. The reaction mixture is stirred at RT for 18h. The solid is removed by filtration and rinsed with dioxane (0.5 L).The filtrate is concentrated under reduced pressure to remove theorganic solvent. The aq. residue is extracted with DCM (2×1 L). Thecombined organic extracts are washed with saturated aq. NaHCO₃ solution(2 L), dried over Na₂SO₄ and filtered. The filtrate is concentratedunder reduced pressure to afford 226 g of2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionic acid ethylester. Yield: 92%; ESI-MS: 291 [M+H]⁺

Step 4: 2-Methyl-2-(3-methyl-butane-1-sulfonyl)-propionic acid

To a solution of 170 g (0.59 mol) of2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionic acid ethylester in THF (3.4 L) are added 225.4 g (1.76 mol) of potassiumtrimethylsilanolate in portions over 0.5 h. The reaction is stirred atroom temperature for 18 h. The reaction mixture is acidified with 2 Maq. HCl solution (2 L) to pH 2 and extracted with DCM (2×2 L). Thecombined organic extracts are dried (Na₂SO₄) and filtered. The filtrateis concentrated under reduced pressure to afford 143 g of2-methyl-2-(3-methyl-butane-1-sulfonyl)-propionic acid. Yield: 93%;ESI-MS: 261 [M−H]⁻

Intermediate 6 2-(5-Amino[1,3,4]thiadiazol-2-yl)-2-methyl-propionitrile

300 mg (3.29 mmol) of thiosemicarbazide and 370 mg (3.27 mmol) of2-Cyano-2-methylpropanoic acid are dissolved in dioxane (10.0 mL) andheated to 90° C. 300 μL (3.29 mmol) of POCl₃ are added dropwise. Thereaction is stirred at 90° C. for 1 h, cooled to RT and diluted with 1 Naq. HCl and DCM. The aq. layer is separated, 4 N aq. NaOH is added toreach pH 8 and then extracted with DCM. Then combined organic layer iswashed with brine and dried. The solvent is removed under reducedpressure to afford 180 mg of2-(5-amino[1,3,4]thiadiazol-2-yl)-2-methyl-propionitrile. Yield: 32%;ESI-MS: 169 [M+H]⁺; HPLC (Rt): 0.24 min (method B)

Intermediate 7 2-(5-Amino-isoxazol-3-yl)-2-methyl-propionitrile

Step 1: 3-Amino-4,4-dimethyl-pent-2-endinitrile

A solution of potassium tert amylate in toluene (25%, 11.8 mL, 23 mmol)is added slowly to a solution of 2,2-Dimethyl-malononitrile (2.0 g, 21mmol) and acetonitrile (1.2 mL, 23 mmol) in toluene (20 mL) at 40° C.under argon. The reaction mixture is stirred at 40° C. for 2 h and thencooled to 12° C. Water (5 mL) is added and the mixture is stirred at 20°C. for 15 min and at 2° C. for 30 min. Filtration, washing with coldwater (10 mL) and drying under vacuum provides 2.30 g3-Amino-4,4-dimethyl-pent-2-endinitrile. Yield: 80%: ESI-MS: 136 [M+H]⁺;¹H-NMR (DMSO-d6): 1.5, 4.1, 6.8 ppm.

Step 2: 2-(5-Amino-isoxazol-3-yl)-2-methyl-propionitrile

To 3-Amino-4,4-dimethyl-pent-2-endinitrile (10.0 g, 74 mmol) in MeOH(150 mL) is added NH₂OH·HCl (10.0 g, 144 mmol). The mixture is stirredat 40° C. for 7 h, concentrated, suspended in isopropyl acetate (100 mL)and washed with 4 N aq. NaOH (2×100 mL) and brine (50 mL). The extractedorg. layer is concentrated to provide 7.40 g of2-(5-Amino-isoxazol-3-yl)-2-methyl-propionitrile. Yield: 66%; ESI-MS:152 [M+H]⁺; ¹H-NMR (DMSO-d6): 1.6, 5.1, 6.8 ppm.

Preparation of Compounds of the Present Invention Example 7N-[5-(Cyano-dimethyl-methyl)-[1,3,4]thiadiazol-2-yl]-2-methyl-2-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-propionamide

To 270 mg (1.25 mmol) of2-methyl-2-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid(intermediate 3) in DMF (3 mL) are added 450 μL (2.58 mmol) DIPEA and480 mg (1.26 mmol) HATU. In a second flask 110 mg sodium hydride (60%dispersion in oil; 2.75 mmol) are added to 215 mg (1.27 mmol)2-(5-amino[1,3,4]thiadiazol-2-yl)-2-methyl-propionitrile (intermediate6) in DMF (3 mL). After 10 min this mixture is added to the activatedacid. The reaction mixture is stirred for additional 30 min, thenfiltered and purified by HPLC-MS to afford 50 mg ofN-[5-(cyano-dimethyl-methyl)-[1,3,4]thiadiazol-2-yl]-2-methyl-2-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-propionamide.

Yield: 11%; ESI-MS: 366 [M+H]⁺; HPLC (Rt): 0.84 min (method A); ¹H-NMR(400 MHz, DMSO-d6): 0.92-1.04 (m, 2H), 1.25 (s, 6H), 1.68-1.76 (m, 3H),1.83 (s, 6H), 2.09 (d, J=6.53 Hz, 2H), 2.20 (s, 3H), 3.23-3.33 (m, 4H),3.79 (dd, J=11.6, 3.5 Hz, 2H), 11.55 (s, 1 H) ppm.

The following examples are prepared in analogy to the above describedprocedure.

Yield ESI-MS ¹H-NMR (400 MHz, Example Structure (%) [M + H]⁺ HPLC (Rt)DMSO-d6): 8

 6 429 0.32 min (method B) 1.30 (s, 6H), 1.60-1.79 (m, 4H), 1.83 (s,6H), 2.19 (s, 3H), 2.50-2.63 (m,1H) 2.65-2.74 (m, 2H), 2.81 (s, 3H),3.51-3.58 (m, 2H), 11.80 (s, 1H) ppm. 4

16 349 0.74 min (method H) 0.91-1.04 (m, 2H), 1.19 (s, 6H), 1.68-1.75(m, 3H), 1.69 (s, 6H), 2.05 (d, J = 6.38 Hz, 2H), 2.16 (s, 3H),3.24-3.30 (m, 2H), 3.81 (dd, J = 11.4, 3.6 Hz, 2H), 6.44 (s, 1H), 10.9(s, 1H) ppm. 5

30 412 0.66 min (method H) 1.25 (s, 6H), 1.62-1.78 (m, 4H), 1.69 (s,6H), 2.17 (s, 3H), 2.50-2.55 (m, 1H), 2.65-2.74 (m, 2H), 2.81 (s, 3H),3.51-3.58 (m, 2H), 6.44 (s, 1H), 11.15 (s, 1H) ppm.

Example 1N-[3-(Cyano-dimethyl-methyl)-isoxazol-5-yl]-2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionamide

To 100 mg (0.38 mmol) of2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionic acid(intermediate 5) in toluene (4.07 mL) are added 55.3 μL (0.76 mmol)thionyl chloride and 3.10 μL (0.04 mmol) DMF. The solution is stirred atreflux for 1 h. In a second flask 78.7 μL (0.46 mmol) DIPEA are added to63.4 mg (0.42 mmol) of 2-(5-amino-isoxazol-3-yl)-2-methyl-propionitrile(intermediate 7) in toluene (2.03 mL). The mixture is stirred at RT for5 min, then added to the acid chloride and stirring is continued at RTfor 16 h. The reaction mixture is purified by HPLC-MS to afford 78.7 mgofN-[3-(cyano-dimethyl-methyl)-isoxazol-5-yl]-2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionamide.Yield: 52%; ESI-MS: 396 [M+H]⁺; HPLC (Rt): 1.14 min (method G); ¹H-NMR(400 MHz, DMSO-d6): 1.68 (s, 6H), 1.70 (s, 6H), 1.86-1.91(m, 2H),2.47-2.52 (m, 2H), 3.34-3.40 (m, 2H), 6.57 (s, 1H), 11.64 (s, 1H) ppm.

Example 2N-[3-(Cyano-dimethyl-methyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionamide

Prepared according to procedure of example 1 starting from 100 mg (0.40mmol) of 2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionicacid (intermediate 2) and 66.4 mg (0.44 mmol)2-(5-amino-isoxazol-3-yl)-2-methyl-propionitrile (intermediate 7).

Yield: 48%; ESI-MS: 384 [M+H]⁺; HPLC (Rt): 0.96 min (method G); ¹H-NMR(400 MHz, DMSO-d6): 1.32-1.42 (m, 2H), 1.67 (s, 6H), 1.70-1.76 (m, 2H),1.70 (s, 6H), 2.12-2.24 (m, 1H), 2.48-2.51 (m, 2H), 3.19 (d, J=6.81 Hz,2H), 3.26-3.34 (m, 2H), 6.59 (s, 1H), 11.57 (s, 1H) ppm.

Example 6 (S)-1-(Tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylicacid[3-(cyano-dimethyl-methyl)-isoxazol-5-yl]-amide

Step 1: (S)-1-(Tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid

To L-proline (1.00 g; 8.69 mmol) in 1,2-dichloroethane (10 mL) aceticacid (1.98 mL; 33.0 mmol)) is added tetrahydro-pyran-4-one (0.87 g; 8.69mmol) and Na₂SO₄ (˜10 equivalents). After 45 minutes of agitation on anorbital shaker, Mp-triacetoxyborohydride resin (4.27 g; 10.42 mmol) isadded. The mixture is agitated at RT overnight and filtered and theresin washed with DCM. The combined filtrate is washed with aq. sat.NaHCO₃ solution and brine, dried (Na₂SO₄), filtered and concentrated invacuo. Excess acetic acid is removed by successive azeotropicdistillation with toluene on the rotary evaporator to afford(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid. ESI-MS: 200[M+H]⁺

Step 2: (S)-1-(Tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid(3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl)-amide

To 1.20 g (6.02 mmol) of(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid in DMF (50mL) are added 3.67 mL (21.1 mmol) diisopropyl-ethyl-amine and 3.44 g(9.03 mmol) of HATU. The solution is stirred at RT for 1 h. In a secondflask to 1.45 g (6.02 mmol) of3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-ylamine(intermediate 7a) in DMF (25 mL) are added 602 mg sodium hydride (60%dispersion in oil; 15.1 mmol) under cooling by an ice bath. Then thissolution is added to the activated acid and stirring is continued for 48h. The reaction mixture is purified by HPLC-MS to afford 0.51 g of(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid(3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl)amide.Yield: 20%; ESI-MS: 422 [M+H]⁺; HPLC (Rt): 1.55 min (method C)

Step 3: (S)-1-(Tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-amide

To 400 mg (0.95 mmol) of(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid(3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl)-amidein EtOH (6.00 mL) are added 119 mg (0.47 mmol)pyridinium-p-toluenesulfonate. The reaction is stirred at 75° C. for 28h. The reaction mixture is purified by HPLC-MS to afford 240 mg of(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-amide. Yield: 75%;ESI-MS: 338 [M+H]⁺; HPLC (Rt): 0.82 min (method D)

Step 4: (S)-1-(Tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid[3-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-amide

To 180 mg (0.53 mmol) of(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-amide in DCM (1.74 mL)are added 317 mg (0.75 mmol) of(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one(Dess-Martin-periodinane). The reaction mixture is stirred at RT for 1h, diluted with sat. aq. NaHCO₃ solution and stirred for additional 30min. The layers are separated; the organic layer is washed with brineand dried over Na₂SO₄. The solvent is removed under reduced pressure,the residue is purified by silica gel chromatographie (eluent: EE) toafford 93.0 mg of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylicacid [3-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-amide. Yield: 52%;ESI-MS: 336 [M+H]⁺; HPLC (Rt): 1.12 min (method E)

Step 5: (S)-1-(Tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid[3-(2-hydroxyimino-1,1-dimethyl-ethyl)-isoxazol-5-yl]-amide

To 90.0 mg (0.27 mmol) of(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid[3-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-amide in MeOH (3.00 mL) areadded 22.4 mg (0.32 mmol) hydroxylamine hydrochloride and 58.5 μL (0.72mmol) pyridine. The reaction is stirred at 60° C. for 3 h. The solventis removed under reduced pressure and the residue is purified by HPLC-MSto afford 79.0 mg of(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid[3-(2-hydroxyimino-1,1-dimethyl-ethyl)-isoxazol-5-yl]-amide. Yield: 84%;ESI-MS: 351 [M+H]⁺; HPLC (Rt): 1.04 min (method E)

Step 6: (S)-1-(Tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylicacid[3-(cyano-dimethyl-methyl)-isoxazol-5-yl]-amide

79.0 mg (0.23 mmol) of(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid[3-(2-hydroxyimino-1,1-dimethyl-ethyl)-isoxazol-5-yl]-amide are added to1.00 mL trifluoroacetic anhydride and stirred at 100° C. for 3 h. Thesolvent is removed under reduced pressure. The residue is purified byHPLC-MS to afford 32.6 mg of(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylicacid[3-(cyano-dimethyl-methyl)-isoxazol-5-yl]-amide. Yield: 44%; ESI-MS:333 [M+H]⁺; HPLC (Rt): 0.66 min (method F); ¹H-NMR (400 MHz, DMSO-d6):1.31-1.53 (m, 2H), 1.57-1.65 (m, 1H), 1.69 (s, 6H), 1.69-1.81 (m, 4H),2.01-2.14 (m, 1H), 2.50-2.66 (m, 2H), 3.08-3.14 (m, 1H), 3.20-3.32 (m,2H), 3.47-3.52 (m, 1H), 3.77-3.88 (m, 2H), 6.46 (s, 1H), 9.70 (s, 1H)ppm.

Example 3N-[3-(Cyano-dimethyl-methyl)-isoxazol-5-yl]-2-(tetrahydro-pyran-4-sulfonyl)-propionamide

To 3.43 g (14.6 mmol) 2-Methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionicacid (intermediate 1) in 38 mL toluene and 17 μL pyridine at 90° C. isadded 2.60 g (21.8 mmol) SOCl₂ dropwise within 20 min and stirring iscontinued for 2 h at 90° C. The solvent is evaporated under reducedpressure and the residue is coevaporated twice with toluene (16 mL each)to afford the crude acid cloride. To 2.00 g2-(5-Amino-isoxazol-3-yl)-2-methyl-propionitrile (13.2 mmol,intermediate 7) in 14 mL toluene is added 3.80 mL (21.8 mmol) DIPEA. Tothis mixture at 60° C. is added dropwise a mixture of the acid chloridein 16 mL toluene within 10 min and stirring is continued overnight at50° C. After addition of water (24 mL) the mixture is heated to 70° C.for 2 h and then allowed to cool to RT. The precipitate is filtered,washed with water (2×8 mL) and dried at 50° C. to afford 3.43 g ofN-[3-(Cyano-dimethyl-methyl)-isoxazol-5-yl]-2-(tetrahydro-pyran-4-sulfonyl)-propionamide.

Yield: 70%; ESI-MS: 370 [M+H]⁺; HPLC (Rt): 0.89 min (method F); ¹H-NMR(400 MHz, DMSO-d6): 1.62-1.72 (m, 2H), 1.69 (s, 6H), 1.70 (s, 6H),1.80-1.87 (m, 2H), 3.30-3.42 (m, 3H), 3.86-3.93 (m, 2H), 6.57 (s, 1H),11.57 (s, 1 H) ppm.

The invention claimed is:
 1. A capsule containing

or a pharmaceutically acceptable salt thereof.
 2. The capsule of claim1, wherein the capsule contains from 1 mg to 1000 mg of

or a pharmaceutically acceptable salt thereof.
 3. The capsule of claim1, wherein the capsule contains from 25 mg to 500 mg of

or a pharmaceutically acceptable salt thereof.
 4. The capsule of claim1, wherein the capsule contains


5. The capsule of claim 1, wherein the capsule contains from 1 mg to1000 mg of


6. The capsule of claim 1, wherein the capsule contains from 25 mg to500 mg of


7. A pill containing

or a pharmaceutically acceptable salt thereof.
 8. The pill of claim 7,wherein the pill contains from 1 mg to 1000 mg of

or a pharmaceutically acceptable salt thereof.
 9. The pill of claim 7,wherein the pill contains from 25 mg to 500 mg of

or a pharmaceutically acceptable salt thereof.
 10. The pill of claim 7,wherein the pill contains


11. The pill of claim 7, wherein the pill contains from 1 mg to 1000 mgof


12. The pill of claim 7, wherein the pill contains from 25 mg to 500 mgof


13. A tablet containing

or a pharmaceutically acceptable salt thereof.
 14. The tablet of claim13, wherein the tablet contains from 1 mg to 1000 mg of

or a pharmaceutically acceptable salt thereof.
 15. The tablet of claim13, wherein the tablet contains from 25 mg to 500 mg of

or a pharmaceutically acceptable salt thereof.
 16. The tablet of claim13, wherein the tablet contains


17. The tablet of claim 13, wherein the tablet contains from 1 mg to1000 mg of


18. The tablet of claim 13, wherein the tablet contains from 25 mg to500 mg of